Cimicifuga racemosa transfer from OTC drug to dietary supplement status requested.

CIMICIFUGA RACEMOSA TRANSFER FROM OTC DRUG TO DIETARY SUPPLEMENT STATUS is requested by Direct Pharmaceuticals Limited in a July 24 citizen petition to FDA. Valletta, Malta-based Direct Pharmaceuticals is asking the agency to delete the ingredient cimicifuga racemosa from the OTC menstrual drug products monograph and instead consider it a dietary supplement in the "appropriate dietary supplement rulemaking" under the Dietary Supplement Health & Education Act. The Direct Pharmaceuticals submission was filed in conjunction with Schaper & Brummer GmbH, the manufacturer of the product.

Cimicifuga racemosa was listed as a Category II (not safe and effective) ingredient in the November 1988 OTC menstrual drugs tentative final monograph. Direct Pharmaceuticals pointed out that the FDA review panel on OTC miscellaneous internal drug products discussed cimicifuga racemosa in 1982 and determined that available data did not support its safety and efficacy. According to the petition, the panel decided that, "while a 150-year history of use of this fluid extract at levels of up to 890 mg a day gives some reassurance of the safety of this compound, additional safety testing, particularly chronic animal studies, is necessary."

The ingredient remained listed as a Category II product in the menstrual products TFM because no submissions on cimicifuga racemosa were made after the 1982 panel report, the petition says.

Direct Pharmaceuticals noted that DSHEA "provides an opportunity for immediate marketing of Remifemin (cimicifuga racemosa) as a dietary supplement" assuming that several requirements are met under the provisions of the new law.

For instance, the company said Remifemin could be marketed if FDA were supplied information prior to marketing that supports the product's reasonable safety and efficacy. The company noted that DSHEA also allows a petition process under which safe conditions for use can be established by regulation, and permits claims about the product's effect on the structure or function of the body.

FDA was notified in January that Vitamer, the division of Anabolic, Inc. that will be the U.S. marketer of the product, would be making a statement of nutritional support for Remifemin. Vitamer said it will claim that Remifemin can relieve the "uncomfortable effects of menopause" and provide a "safe and easy way to adjust to lower estrogen levels" ("The Tan Sheet" July 17, p. 11). The submission to FDA also provided a summary of clinical data on the ingredient.

To support its request, Direct Pharmaceuticals submitted a dossier prepared by Schaper & Brummer that includes drug indication information and study data on cimicifuga racemosa as a dietary supplement for estrogen deficiency.

The company explained that "substances from cimicifuga racemosa bind to estrogen receptors and reduce the secretion of the luteinizing hormone without influencing the hypophyseal release of follicle stimulating hormone" and thereby reduce the symptoms related to estrogen deficiency. In short, the petitioner claimed, "phytoestrogens from Remifemin provide an estrogen `lift' to make up for the lack of the hormone."

Regarding the safety of cimicifuga racemosa, Direct Pharmaceuticals reported that a six-month chronic oral toxicity test in female Wistar rats was contracted by Schaper & Brummer in 1991. However, Schaper & Brummer said it would draw only "limited conclusions as to the effects of Remifemin granulate on the respiratory and circulatory system" from the results of the study.

Based on "clinical observations and studies conducted during the past 30 years," Direct Pharmaceuticals maintained that the action of Remifemin "does not have an immediate onset" and that its benefit may be dependent on use for periods as long as four weeks. "The first estrogen deficiency relief becomes apparent after two weeks' use," the firm said.

Direct Pharmaceuticals also provided proposed labeling for Remifemin, which states that the product is intended for use in "normal estrogen deficiency." The company added that the stability of Remifemin tablets is limited to two years. The petition claims that the deletion of cimicifuga racemosa from the OTC drug rulemaking "will relieve the FDA as well as industry from the burden of submitting and reviewing repetitive" NDAs and ANDAs.